The respiratory syncytial virus (RSV) prefusion F-protein functional antibody repertoire in adult healthy donors.
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ABSTRACT:
SUBMITTER: Andreano E
PROVIDER: S-EPMC8185550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-29 | GSE232687 | GEO
Project description:Live-attenuated pediatric vaccines for intranasal administration are being developed for human respiratory syncytial virus (RSV), an important worldwide pediatric respiratory pathogen that lacks a licensed vaccine or suitable antiviral drug. We evaluated a prime-boost strategy in which primary immunization with RSV was boosted by secondary immunization with RSV or with a chimeric recombinant bovine/human parainfluenza virus type 3 (rB/HPIV3) vector expressing the RSV fusion F protein. The vector-expressed F protein had been engineered (DS-Cav1 mutations) for increased stability in the highly immunogenic prefusion (pre-F) conformation, with or without replacement of its transmembrane and cytoplasmic tail domains with their counterparts from bovine parainfluenza virus type 3 (BPIV3) F protein to direct incorporation into the vector virion for increased immunogenicity. In hamsters that received a primary infection with RSV, a booster infection with RSV ∼6 weeks later was completely restricted for producing infectious virus but induced a significant increase in the serum RSV-plaque-reduction neutralizing antibody titer (RSV-PRNT). Boosting instead with the rB/HPIV3-RSV-pre-F vectors resulted in efficient replication and induced significantly higher RSV-PRNTs than RSV. In African green monkeys that received a primary infection with RSV, a booster infection with RSV ∼2, ∼6, or ∼15 months later was highly restricted, whereas booster infections with the vectors had robust replication. Compared with RSV, boosts with the vectors induced 7- to 15-fold higher titers of RSV-specific serum antibodies with high neutralizing activity, as well as significantly higher titers of RSV-specific mucosal IgA antibodies. These findings support further development of this heterologous prime-boost strategy.IMPORTANCE Immune responses to RSV in infants can be reduced due to immunological immaturity and immunosuppression by RSV-specific maternal antibodies. In infants and young children, two infections with wild-type RSV typically are needed to achieve the titers of RSV-specific serum antibodies and protection against illness that are observed in adults. Therefore, a boost might substantially improve the performance of live pediatric RSV vaccines presently being developed. Hamsters and African green monkeys received a primary intranasal infection with RSV and were given a boost with RSV or a parainfluenza virus (PIV) vector expressing RSV fusion protein engineered for enhanced immunogenicity. The RSV boost was highly restricted but induced a significant increase in serum RSV-neutralizing antibodies. The PIV vectors replicated efficiently and induced significantly higher antibody responses. The use of an attenuated PIV vector expressing RSV antigen to boost a primary immunization with an attenuated RSV warrants further evaluation.
| S-EPMC7944453 | biostudies-literature
Project description:BACKGROUND:Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia in children. RSV-specific antibody (ab) protects infants from disease, and may be increased by a potential strategy of maternal RSV vaccination. OBJECTIVES:To describe the effect of RSV antibody on RSV infection risk in infants in a resource-limited setting. STUDY DESIGN:In a prospective study in Nepal, women were enrolled during pregnancy and maternal and infant cord blood were collected at birth. Weekly surveillance for respiratory illness was performed from birth to 180days. Nasal swabs were tested for RSV by PCR and serum was tested using an RSV antibody microneutralization assay. Antibody concentrations at time of RSV infection were estimated based on a decay rate of 0.026 log2/day. RESULTS:Cord:maternal RSV antibody transfer ratio was 1.03 (0.88-1.19), with RSV antibody concentration of log2 11.3 and log2 11.7 in 310 paired maternal and infant samples, respectively. Cord blood RSV antibody was log2 12.1 versus 11.6 in those with or without RSV infection (P=0.86). Among infants with RSV infection, estimated RSV antibody concentration at time of infection did not differ in infants with upper (n=8; log2 10.7) versus lower respiratory tract infection (n=21; log2 9.8; P=0.37). Cord blood RSV antibody concentrations did not correlate with age at primary RSV infection (R=0.11; P=0.57). CONCLUSIONS:Transplacental transfer of RSV antibody from mother to the fetus was highly efficient in mother-infant pairs in rural Nepal, though higher antibody concentrations were not protective against earlier or more severe RSV infection in infants.
| S-EPMC5625849 | biostudies-literature
Project description:Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.).
| S-EPMC5328523 | biostudies-literature
Project description:Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infection in infants. Immunoprophylaxis with the anti-RSV monoclonal antibody, palivizumab, reduces the risk for RSV-related hospitalizations, but its use is restricted to high-risk infants due to the high costs. In this study, we investigated if genetic delivery of anti-RSV antibody to neonatal mice by chimpanzee adenovirus type 7 expressing the murine form of palivizumab (AdC7αRSV) can provide protection against RSV. Intranasal and intramuscular administration of AdC7αRSV to adult mice resulted in similar levels of anti-RSV IgG in the serum. However, only intranasal administration resulted in detectable levels of anti-RSV IgG in the bronchoalveolar lavage fluid. Intranasal administration of AdC7αRSV provided protection against subsequent RSV challenge. Expression of the anti-RSV antibody was prolonged following intranasal administration of AdC7αRSV to neonatal mice. Protection against RSV was confirmed at 6 weeks of age. These data suggest that neonatal genetic delivery of anti-RSV antibody by AdC7αRSV can provide protection against RSV.
| S-EPMC6466083 | biostudies-other
Project description:Human respiratory syncytial virus (RSV) is the most prevalent worldwide cause of severe respiratory tract infection in infants and young children. Human parainfluenza virus type 1 (HPIV1) also causes severe pediatric respiratory illness, especially croup. Both viruses lack vaccines. Here, we describe the preclinical development of a bivalent RSV/HPIV1 vaccine based on a recombinant HPIV1 vector, attenuated by a stabilized mutation, that expresses RSV F protein modified for increased stability in the prefusion (pre-F) conformation by previously described disulfide bond (DS) and hydrophobic cavity-filling (Cav1) mutations. RSV F was expressed from the first or second gene position as the full-length protein or as a chimeric protein with its transmembrane and cytoplasmic tail (TMCT) domains substituted with those of HPIV1 F in an effort to direct packaging in the vector particles. All constructs were recovered by reverse genetics. The TMCT versions of RSV F were packaged in the rHPIV1 particles much more efficiently than their full-length counterparts. In hamsters, the presence of the RSV F gene, and in particular the TMCT versions, was attenuating and resulted in reduced immunogenicity. However, the vector expressing full-length RSV F from the pre-N position was immunogenic for RSV and HPIV1. It conferred complement-independent high-quality RSV-neutralizing antibodies at titers similar to those of wild-type RSV and provided protection against RSV challenge. The vectors exhibited stable RSV F expression in vitro and in vivo In conclusion, an attenuated rHPIV1 vector expressing a pre-F-stabilized form of RSV F demonstrated promising immunogenicity and should be further developed as an intranasal pediatric vaccine.IMPORTANCE RSV and HPIV1 are major viral causes of acute pediatric respiratory illness for which no vaccines or suitable antiviral drugs are available. The RSV F glycoprotein is the major RSV neutralization antigen. We used a rHPIV1 vector, bearing a stabilized attenuating mutation, to express the RSV F glycoprotein bearing amino acid substitutions that increase its stability in the pre-F form, the most immunogenic form that elicits highly functional virus-neutralizing antibodies. RSV F was expressed from the pre-N or N-P gene position of the rHPIV1 vector as a full-length protein or as a chimeric form with its TMCT domain derived from HPIV1 F. TMCT modification greatly increased packaging of RSV F into the vector particles but also increased vector attenuation in vivo, resulting in reduced immunogenicity. In contrast, full-length RSV F expressed from the pre-N position was immunogenic, eliciting complement-independent RSV-neutralizing antibodies and providing protection against RSV challenge.
| S-EPMC5660469 | biostudies-literature
Project description:Respiratory Syncytial Virus (RSV) is the most common cause of respiratory tract infection in infants and children and shows increasing trend among elderly people worldwide. In many developing country settings, population and household structures have gone through some significant changes in the past decades, namely fewer births, more elderly population, and smaller household size but more RSV high-risk individuals. These dynamics have been captured in a mathematical model with RSV transmission dynamics to predict the disease burden on the detailed population for future targeted interventions. The population and disease dynamics model was constructed and tested against the hospitalization data for Acute Lower Respiratory Tract Infection due to RSV in rural Thai settings between 2005 and 2011. The proportion of extended families is predicted to increase by about 10% from 2005 to 2020, especially for those with elderly population, while the classic nuclear family type (with adults and children) will decline by about 10%. For RSV, infections from extended family type (approximately 60% of all household types) have majorly contributed to the force of infection (FOI). While the model predicted the increase of FOI from the extended family by 15% from 2005 to 2020, the FOI contributed by other household types would be either stable or decrease in the same time period. RSV incidence rate is predominantly high among babies (92.2%) and has been predicted to decrease slightly over time (from 940 to 864 cases per 100,000 population by 2020), while the incidence rates among children and elderly people may remain steadily low over the same period. However, the estimated incidence rates among elderly people were twice than those in children. The model predicts that approximately 60% of FOI for RSV will come from members of the extended family type. The incidence rate of RSV among children and elderly in extended families was about 20 times lower than that in infants and the trend is steady. Targeted intervention strategies, such as health education in some specific groups and targeted vaccination, may be considered, with the focus on extended family type. Target interventions on babies can lessen the transmission to children and elderly especially when transmission within households of extended family type is high.
| S-EPMC6615606 | biostudies-literature
Project description:Respiratory syncytial virus (RSV) is the primary cause for acute lower respiratory syndrome in children younger than 5 years. Research on B cell repertoires and antibodies binding the RSV fusion protein (RSV F) is of major interest in the development of potential vaccine candidates and therapies. B cell receptors (BCRs) which have higher affinities for a specific antigen are preferentially selected for B cell clonal expansion in germinal center reactions. Consequently, antigen-specific BCR repertoires share common features, as for instance preferential variable gene usage, variable region mutation levels or lengths of the heavy chain complementarity-determining region 3. Since RSV repeatedly infects every person throughout life, memory B cells (MBC) expressing RSV F-binding BCRs circulate in the blood of healthy adults. This dataset of BCR variable region sequence features was derived from single cell-sorted RSV F-directed MBCs of a healthy adult blood donor [1]. The dataset was produced with publicly available data analysis software programs and scripts, which facilitates integration or comparison with antibody sequence repertoire data of different individuals derived with the same or comparable data analysis approaches and tools.
| S-EPMC7666335 | biostudies-literature
Project description:Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are the first and second leading viral agents of severe respiratory tract disease in infants and young children worldwide. Vaccines are not available, and an RSV vaccine is particularly needed. A live attenuated chimeric recombinant bovine/human PIV3 (rB/HPIV3) vector expressing the RSV fusion (F) glycoprotein from an added gene has been under development as a bivalent vaccine against RSV and HPIV3. Previous clinical evaluation of this vaccine candidate suggested that increased genetic stability and immunogenicity of the RSV F insert were needed. This was investigated in the present study. RSV F expression was enhanced 5-fold by codon optimization and by modifying the amino acid sequence to be identical to that of an early passage of the original clinical isolate. This conferred a hypofusogenic phenotype that presumably reflects the original isolate. We then compared vectors expressing stabilized prefusion and postfusion versions of RSV F. In a hamster model, prefusion F induced increased quantity and quality of RSV-neutralizing serum antibodies and increased protection against wild-type (wt) RSV challenge. In contrast, a vector expressing the postfusion F was less immunogenic and protective. The genetic stability of the RSV F insert was high and was not affected by enhanced expression or the prefusion or postfusion conformation of RSV F. These studies provide an improved version of the previously well-tolerated rB/HPIV3-RSV F vaccine candidate that induces a superior RSV-neutralizing serum antibody response.Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are two major causes of pediatric pneumonia and bronchiolitis. The rB/HPIV3 vector expressing RSV F protein is a candidate bivalent live vaccine against HPIV3 and RSV. Previous clinical evaluation indicated the need to increase the immunogenicity and genetic stability of the RSV F insert. Here, we increased RSV F expression by codon optimization and by modifying the RSV F amino acid sequence to conform to that of an early passage of the original isolate. This resulted in a hypofusogenic phenotype, which likely represents the original phenotype before adaptation to cell culture. We also included stabilized versions of prefusion and postfusion RSV F protein. Prefusion RSV F induced a larger quantity and higher quality of RSV-neutralizing serum antibodies and was highly protective. This provides an improved candidate for further clinical evaluation.
| S-EPMC4542370 | biostudies-literature
Project description:BackgroundNeutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary.MethodsFive decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population.FindingsThe MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants.InterpretationAn MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.
| S-EPMC8603022 | biostudies-literature